Tissue factor (TF) is a cell surface receptor responsible for initiation of the coagulation cascades. The extracellular domain of TF mediates protein-protein interactions with factor VIIa which results in enhancement of the catalytic activity of factor VIIa towards small peptidyl substrates. TF also mediated the assembly of the ternary complex with macromolecular substrates factors IX and X that is necessary for proteolytic activation of these zymogens. Structural characterization of TF, and elucidation of the molecular interactions involved in assembly of the binary complex with factor VIIa and the ternary complex with substrate, is central to understanding the underlying molecular events involved in initiation of the coagulation protease cascades. State-of-the-art multi-dimensional heteronuclear NMR methods will be used to determine the solution structure and flexibility of the extracellular domain of TF and of small domains of factor VIIa that bind to TF. NMR will also be used to map the surfaces of these domains involved in assembly of the TF-VIIa complex and in recognition of protein substrate factor X. The resulting structural knowledge will provide important new insights into the molecular recognition events that initiate thrombogenesis and may, in long term, form the basis for design of novel therapeutic agents that inhibit the TF induced coagulation associated with arterial thrombosis, septic shock and tumor metastasis.